Nembhard Wendy N, Tang Xinyu, Hu Zhuopei, MacLeod Stewart, Stowe Zachary, Webber Daniel
Division of Birth Defects Research, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences and Arkansas Children's Research Institute, Little Rock, AR, 72202, USA
Division of Biostatistics, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Arkansas Children's Research Institute, Little Rock, AR, 72202 USA.
BMJ. 2017 Mar 6;356:j832. doi: 10.1136/bmj.j832.
To evaluate whether the association between maternal periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and increased risk of congenital heart defects in offspring is modified by maternal or infant genetic variants in folate, homocysteine, or transsulfuration pathways. Population based study. DNA from mothers, fathers, and infants was genotyped with an Illumina GoldenGate custom single nucleotide polymorphism panel. A hybrid design based on a log linear model was used to calculate relative risks and Bayesian false discovery probabilities (BFDP) to identify polymorphisms associated with congenital heart defects modified by SSRI use. Data from the US National Birth Defects Prevention Study on 1180 liveborn infants with congenital heart defects and 1644 controls, born 1997-2008. Cases included infants with selected congenital heart defects and control infants had no major defects. SSRI use was obtained from telephone interviews with mothers. For women who reported taking SSRIs periconceptionally, maternal SHMT1 (rs9909104) GG and AGgenotypes were associated with a 5.9 and 2.4 increased risk of select congenital heart defects in offspring, respectively, versus the AA genotype (BFDP=0.69). Compared with the AA genotype, BHMT (rs492842 and rs542852) GG and AG genotypes were associated with twice the riskof congenital heart defects (BFDP=0.74 and 0.79, respectively). MGST1 (rs2075237) CC and ACgenotypes were associated with an increased risk compared with the GG genotype (8.0 and 2.8, respectively; BFDP=0.79). Single nucleotide polymorphism in infant genes in the folate (MTHFS rs12438477), homocysteine (TRDMT1 rs6602178 and GNMT rs11752813) and transsulfuration (GSTP1 rs7941395 and MGST1 rs7294985) pathways were also associated with an increased risk of congenital heart defects. Common maternal or infant genetic variants in folate, homocysteine, or transsulfuration pathways are associated with an increased risk of certain congenital heart defects among children of women taking SSRIs during cardiogenesis.
评估孕期使用选择性5-羟色胺再摄取抑制剂（SSRI）与后代先天性心脏缺陷风险增加之间的关联是否会因母亲或婴儿在叶酸、同型半胱氨酸或转硫途径中的基因变异而改变。基于人群的研究。使用Illumina GoldenGate定制单核苷酸多态性芯片对母亲、父亲和婴儿的DNA进行基因分型。基于对数线性模型的混合设计用于计算相对风险和贝叶斯错误发现概率（BFDP），以识别与SSRI使用所改变的先天性心脏缺陷相关的多态性。来自美国国家出生缺陷预防研究的数据，涉及1997 - 2008年出生的1180例患有先天性心脏缺陷的活产婴儿和1644例对照。病例包括患有特定先天性心脏缺陷的婴儿，对照婴儿无重大缺陷。通过对母亲的电话访谈获取SSRI使用情况。对于报告孕期使用SSRI的女性，母亲丝氨酸羟甲基转移酶1（SHMT1，rs9909104）的GG和AG基因型与后代特定先天性心脏缺陷风险分别增加5.9倍和2.4倍相关，而AA基因型（BFDP = 0.69）。与AA基因型相比，甜菜碱同型半胱氨酸甲基转移酶（BHMT，rs492842和rs542852）的GG和AG基因型与先天性心脏缺陷风险增加两倍相关（BFDP分别为0.74和0.79）。微粒体谷胱甘肽S转移酶1（MGST1，rs2075237）的CC和AC基因型与GG基因型相比风险增加（分别为8.0和2.8；BFDP = 0.79）。叶酸（亚甲基四氢叶酸合酶MTHFS，rs12438477）、同型半胱氨酸（转甲基转移酶1 TRDMT1，rs6602178和甘氨酸N-甲基转移酶GNMT，rs11752813）和转硫途径（谷胱甘肽S转移酶P1 GSTP1，rs7941395和微粒体谷胱甘肽S转移酶1 MGST1，rs7294985）中婴儿基因的单核苷酸多态性也与先天性心脏缺陷风险增加相关。在心脏发生过程中使用SSRI的女性所生子女中，叶酸、同型半胱氨酸或转硫途径中常见的母亲或婴儿基因变异与某些先天性心脏缺陷风险增加相关。
